Neuropathic pain can be described as pain associated with damage or permanent alteration of the peripheral or central nervous system. Clinical manifestations of neuropathic pain include a sensation of burning or electric shock, feelings of bodily distortion, allodynia and hyperalgesia.
Sodium channel-blocking agents have been reported to be effective in the treatment of various disease states, and have found particular use as local anesthetics and in the treatment of cardiac arrhythmias. It has also been reported for many years that sodium channel-blocking agents may also be useful in the treatment of pain, including neuropathic pain; see for example, Tanelian et al. Pain Forum. 1995, 4(2), 75-80. Preclinical evidence demonstrates that sodium channel-blocking agents selectively suppress abnormal ectopic neural firing in injured peripheral and central neurons, and it is via this mechanism that they are believed to be useful for relieving pain. Consistent with this hypothesis, it has been shown that sodium channels accumulate in the peripheral nerve at sites of axonal injury (Devor et al. J. Neurosci. 1993, 132, 1976-1992). Alterations in either the level of expression or distribution of sodium channels within an injured nerve, therefore, have a major influence on the pathophysiology of pain associated with this type of trauma. This concept is supported by the relative success of employing sodium channel modulating agents (e.g., anticonvulsants, local anesthetics) for the treatment of neuropathic pain. However, pain relief has often been obtained concomitantly with numerous adverse events and/or limitations in efficacy which have restricted tolerability of these drugs. It can be seen that a need still exists for an orally active agent that is effective for the treatment of neuropathic pain, but having fewer side effects.
Various phenoxymethyl piperidine derivatives have been described in the patent and non-patent literature. For example, PCT Published Application Nos. WO 92/02501 (Smithkline & French) and WO 93/15052 (Smithkline Beecham) generically discloses various optionally substituted 3-phenoxymethyl piperidine and 3-phenoxyethyl piperidine derivatives, respectively, useful as calcium channel blocking agents.
U.S. Pat. No. 3,634,437 (Todd) discloses optionally substituted 3-phenoxymethyl piperidine compounds, which may be used in the treatment of depressive illness, anxiety, neurotic states and epilepsy. U.S. Pat. No. 3,709,892 (Leeming et al.) discloses substituted 3-phenoxyalkylamines, for example, 3-[(2-cyclohexylethyl)phenoxymethyl]-1 -methylpiperidine, which possess gastric antisecretory activity. U.S. Pat. Nos. 4,877,799; 4,985,446; and 5,019,582 (Drejer et al.); and U.S. Pat. Nos. 5,158,961 and 5,227,379 (Jakobsen et al.) disclose 4-phenyl-3-phenoxymethyl piperidine derivatives as calcium overload inhibitors useful in the treatment of anoxia, ischemia, migraine and epilepsy.
U.S. Pat. No. 4,508,724 (Taylor et al.) discloses 3-phenoxymethyl-3-piperidinol derivatives having antiarrhythmic, antidepressant and antihypertensive activity. U.S. Pat. No. 4,822,778 (Aberg et al.) discloses optionally substituted 2-phenoxymethyl piperidine derivatives, particularly N-methyl-2-[(2,6-xyloxy)methyl]-piperidine, having anesthetic and antiarrhythmic activity.
Arya et al. Indian J. Chem. 1977, 15B, 1125-1128 describes the synthesis and pharmacological activity of piperidyl ethers, particularly 3-(4-fluorophenoxymethyl)-1-methylpiperidine, as central nervous system depressants. Balsamo et al. J. Med. Chem. 1987, 30, 222-225, describes the synthesis and antidepressant activity of 3-[(2-ethoxyphenoxy)methyl]-piperidine derivatives.
The disclosures of these and other documents referred to throughout this application are incorporated herein by reference.